Spliceosomal Modulators Display Anti‐Melanoma Efficacy in a BRAF Inhibitor‐Resistant Xenograft Model and Increase Tumor Immunogenicity in a Syngeneic Mouse Melanoma Model

Melanoma is one of the deadliest cancers and remains a major clinical challenge, especially in advanced stages where conventional therapies often show limited effectiveness. For example, one of the issues that melanoma patients face in clinics is acquired resistance to BRAF inhibitor therapy. We have previously reported that targeting spliceosomal proteins with small molecules results in apoptosis in melanomas. In the present study, the antimelanoma efficacy of our lead compounds 2155-14 and 2155-18 was evaluated by testing them in BRAF inhibitor-resistant A375R cell-line xenograft in nude athymic mice. Both compounds significantly decreased the growth of A375R tumors, which was comparable to vemurafenib/cobimetinib. Additionally, by using an immunocompetent B16 mouse melanoma model, we detected increased numbers of several immune cell types in tumors, suggesting that the two compounds also increase antimelanoma immune response. In conclusion, these results demonstrate the therapeutic potential of targeting spliceosomal proteins hnRNPH1 and H2 as monotherapy or in combination with immunotherapy.